Fondaparinux (Arixtra®) is a synthetic, highly sulfated pentasaccharide, which has a sequence derived from the minimal antithrombin (AT) binding region of heparin. Fondaparinux is the first in a class of antithrombotic agents known as the selective factor Xa inhibitors (Cardiovasc. Drug Rev. 2002, 20(1):37-52). The clinical use of fondaparinux as an anticoagulant is known (Thromb. Res. 2012, 129(4):407, Curr. Opin. Pulm. Med. 2004, 10(5):338). The use of such agents for the prevention and/or treatment of venous thromboembolism has been reported (Walenga et al., Expert Opin. Investig. Drugs 2002, 11: 397-407; Bauer, Best Practice & Research Clinical Hematology 2004, 17(1): 89-104).
There are several disadvantages of current methods used for the synthesis of fondaparinux sodium. First, published overall yields are low. The synthesis by Sinaÿ's method only provided an overall yield of 0.053% (Carbohydrate Research, 1984, 132(2): C5-C9.). Van Boeckel and co-workers provided a method on reasonable scale (156 mg of final product) overall yield of 0.22% (J. Carbohydrate Chem. 4(3):293-321). Second, stereoselective formation of the 1,2-cis of the α-D-glucosamine glycosidic bond is challenging. Third, published syntheses of fondaparinux contain over 50 synthetic steps (see, U.S. Pat. No. 7,541,445). Fourth, when glucuronic and iduronic acids are employed as glycosyl acceptors in the synthesis, the glycosylation reaction proceeds in low yield and is accompanied by β-elimination side product.
In summary, there are several limitations to current methods of synthesizing fondaparinux in the art. Thus, there is a need for new synthetic procedures that produce fondaparinux, related compounds, and intermediates thereto in an efficient manner.